News / Events

PXL770 observed to have a favorable safety and pharmacokinetic
profile in the complete Phase 1 program

PXL770 is advancing into a Phase 2a proof-of-concept program for
NASH

LYON, France--(BUSINESS WIRE)--
POXEL
SA (Euronext – POXEL - FR0012432516), a biopharmaceutical company
focused on the development of innovative treatments for metabolic
disorders, including type 2 diabetes and non-alcoholic steatohepatitis
(NASH), today announced favorable results from the PXL770 Phase 1b
two-part study that included a multiple ascending dose (MAD) trial and a
drug-drug interaction study. PXL770 is a first-in-class, oral, direct
adenosine monophosphate-activated protein kinase (AMPK) activator that
is advancing into a Phase 2a proof-of-concept program for the treatment
of NASH. Liver diseases, such as NASH, are growing in prevalence, and
there are no regulator-approved treatments available.

“We are pleased with the outcome of the PXL770 Phase 1 program. We
believe that PXL770’s unique mechanism of action has the potential to
treat the underlying root causes of fatty liver diseases, including
liver steatosis, inflammation and fibrosis, as well as provide benefits
for co-morbidities, including those related to cardiovascular disease,”
said Thomas Kuhn, CEO of Poxel. “We are planning to initiate a Phase 2a
program in patients with nonalcoholic fatty liver disease (NAFLD), a
condition in which fat builds up in the liver. We are also exploring
other metabolic diseases for proof-of-concept studies for PXL770.”

The MAD trial included 48 subjects and evaluated the safety,
tolerability and pharmacokinetics (PK) of PXL770 administered once- or
twice-daily after 10-day repeated administration in six dose groups
ranging from 60 mg to 500 mg. In this study, there were no serious
adverse events or adverse events leading to withdrawal. PXL770 was well
tolerated up to the highest dose tested of 500 mg, which was reached
because none of the dose escalation safety stopping criteria was met. In
this study, electrocardiogram (ECG) was investigated at all doses, and
PXL770 did not induce prolongation of the TQT interval (a cardiac safety
measurement), nor changes in any other ECG parameters. The PK (Cmax and
AUC) of PXL770 was shown to be linear with a trend for saturation at the
highest dose tested.

In addition to the MAD trial, a drug-drug interaction study was also
conducted with rosuvastatin, a statin drug and probe substrate for
organic anion transporting polypeptide (OATP) transporters, which can
cause PK drug–drug interactions. In this study 12 subjects were
administered 250 mg doses of PXL770 once-daily and the standard dose of
rosuvastatin. The results demonstrated the lack of PK interaction
between PXL770 and OATP substrates.

Based on the favorable results in the Phase 1b and the favorable safety
and tolerability profile in the single ascending dose Phase 1a study,
the Company is preparing to initiate a Phase 2a proof-of-concept
program. This program will include a randomized, double-blind,
placebo-controlled, parallel-group study that will assess the efficacy
and safety of PXL770 versus placebo in approximately 100 patients with
NAFLD with or without type 2 diabetes. The primary endpoint of the study
will be defined as the relative percent change from baseline in liver
fat content, as assessed using magnetic resonance imaging-estimated
proton density fat fraction (MRI-PDFF) after 12 weeks of treatment.
Secondary parameters will explore the role of PXL770 on lipid metabolism
and glucose control. The Phase 2a program will also include a
mechanistic component that will assess the effect of PXL770 on the
inhibition of lipolysis (release of FFA from triglycerides stored in the
adipose tissue) and hepatic de novo lipogenesis
(triglycerides synthesis from glucose precursors).

During the second half of 2018, preparation for the Phase 2a program for
PXL770 will include filing an Investigational New Drug Application with
the U.S. Food and Drug Administration, manufacturing of drug product and
validation of clinical sites.

Through directly activating AMPK, PXL770 acts on an important biological
target. AMPK is a master regulator of cellular energy and its activation
has the potential to treat numerous chronic metabolic diseases,
including diseases that affect the liver, such as NASH,1
which is a severe form of NAFLD. This target is important because it has
the potential to trigger benefits on the three key pathophysiology
processes involved in NASH development: liver steatosis, inflammation
and fibrosis. PXL770 may also be differentiated from other compounds in
development for liver diseases since AMPK activation has the potential
to also treat NASH comorbidities, specifically targeting cardiovascular
risk factors, such as hyperglycemia, insulin resistance, dyslipidemia,
inflammation and obesity.

In the PXL770 Phase 1a single ascending dose (SAD) study, safety,
tolerability and pharmacokinetics of six doses of PXL770 were assessed
in 64 healthy male subjects. The results demonstrated that PXL770
exhibited a favorable safety and tolerability profile with no serious
adverse events reported nor safety signals. PK assessment showed that
PXL770 plasma exposure (Cmax and AUC) increased in a dose dependent
manner following oral administration with moderate inter-individual
variability.

Data results presented at the Global NASH Congress 2018 in February
highlighted the beneficial effect of AMPK activation in a diet induced
NASH mouse model and the potential of PXL770 to act on liver steatosis
and inflammation as well as adipose tissue lipolysis and inflammation.
This data is available on the Company’s website under “Scientific
Publications” or by using the following link http://www.poxelpharma.com/en_us/product-pipeline/posters.

About NASHNon-alcoholic steatohepatitis (NASH) is a
metabolic disease with no clear disease origin that is quickly becoming
a worldwide epidemic. It is characterized by the accumulation of fat in
the liver causing inflammation and fibrosis. The disease can be silent
for a long period of time, but once it accelerates, severe damage and
liver cirrhosis can occur, which can significantly impact liver function
or can even result in liver failure or liver cancer. Typical risk
factors for NASH include obesity, elevated levels of blood lipids (such
as cholesterol and triglycerides) and diabetes. Currently no curative or
specific therapies are available.

About PXL770PXL770 is a first-in-class direct adenosine
monophosphate-activated protein kinase (AMPK) activator. AMPK is a
central regulator of multiple metabolic pathways leading to the control
of lipid metabolism, glucose homeostasis and inflammation. Based on its
central metabolic role, targeting AMPK offers the opportunity to pursue
a wide range of indications to treat chronic metabolic diseases,
including diseases that affect the liver, such as non-alcoholic
steatohepatitis (NASH).

About Poxel SAPoxel uses its development expertise in
metabolism to advance a pipeline of drug candidates focused on the
treatment of metabolic disorders, including type 2 diabetes and
non-alcoholic steatohepatitis (NASH). We have successfully completed the
Phase 2 clinical program for our first-in-class lead product, Imeglimin,
which targets mitochondrial dysfunction, in the U.S., Europe and Japan.
Together, with our partner Sumitomo Dainippon Pharma, we are conducting
the Phase 3 Trials of IMeglimin for Efficacy
and Safety (TIMES) program for the treatment of type 2
diabetes in Japan.Our partnerRoivant Sciences
will be responsible for Imeglimin’s development and commercialization in
countries outside of Poxel’s partnership with Sumitomo Dainippon Pharma,
including the U.S. and Europe. Our second program, PXL770, a first in
class direct adenosine monophosphate-activated protein kinase (AMPK)
activator, is advancing into a Phase 2a proof-of-concept program for the
treatment of NASH. PXL770 could also have the potential to treat
additional metabolic diseases. We intend to generate further growth
through strategic partnerships and pipeline development. (Euronext:
POXEL, www.poxelpharma.com)